Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes

Yifei Zhong,Shumin Yang,Tianming Wang,Bhaskar Das,Alecia N Muwonge,John Cijiang He,Nicholas J Wong,Xueling Li,Weijia Zhang,Ruijie Liu,Chengguo Wei,Evren U Azeloglu,Kyung Lee,Yueyi Deng,Yiping Chen,Yueming Ma

doi:10.1038/s41467-019-12433-w

Abstract

Arctigenin (ATG) is a major component of Fructus Arctii, a traditional herbal remedy that reduced proteinuria in diabetic patients. However, whether ATG specifically provides renoprotection in DKD is not known. Here we report that ATG administration is sufficient to attenuate proteinuria and podocyte injury in mouse models of diabetes. Transcriptomic analysis of diabetic mouse glomeruli showed that cell adhesion and inflammation are two key pathways affected by ATG treatment, and mass spectrometry analysis identified protein phosphatase 2 A (PP2A) as one of the top ATG-interacting proteins in renal cells. Enhanced PP2A activity by ATG reduces p65 NF-κB-mediated inflammatory response and high glucose-induced migration in cultured podocytes via interaction with Drebrin-1. Importantly, podocyte-specific Pp2a deletion in mice exacerbates DKD injury and abrogates the ATG-mediated renoprotection. Collectively, our results demonstrate a renoprotective mechanism of ATG via PP2A activation and establish PP2A as a potential target for DKD progression.

Highlights

Arctigenin (ATG) is a major component of Fructus Arctii, a traditional herbal remedy that reduced proteinuria in diabetic patients
We show that ATG, used as a single agent, is sufficient to significantly blunt proteinuria and attenuate the kidney disease progression in diabetic mice and that the main mechanism of action is through its binding to and activation of protein phosphatase 2 A (PP2A)
Transmission electron microscopy (TEM) images showed significant podocyte foot process effacement in the diabetic mouse kidneys, which was reversed by ATG treatment (Fig. 2a, b, Supplementary Fig. 1B)

Summary

Introduction

Arctigenin (ATG) is a major component of Fructus Arctii, a traditional herbal remedy that reduced proteinuria in diabetic patients. Histological analysis of periodic acid–Schiff (PAS)-stained kidneys showed that ATG treatment attenuated the glomerular hypertrophy and mesangial matrix expansion in diabetic mice (Fig. 1c, d, Supplementary Fig. 1A). Glomerular injury and podocyte loss was reduced in the db/db mice with the ATG treatment

Results

Conclusion